PROJECT I ? ROLE OF BILIRUBIN IN PROTECTION AGAINST CARDIOMETABOLIC SYNDROME IN OBESITY PROJECT SUMMARY/ABSTRACT Obesity is a significant contributor to cardiometabolic diseases including hypertension, non-alcoholic fatty liver disease (NAFLD) and type II diabetes. All of these conditions contribute to the increased morbidity and mortality rates of obesity. Large population studies have demonstrated a negative correlation between serum bilirubin levels and development of cardiovascular disease and metabolic disorders including NAFLD and type II diabetes. Despite these correlative studies, the mechanism by which bilirubin protects against cardiometabolic disease is not known. We have exciting data demonstrating for the first time that bilirubin signals through nuclear hormone receptors such as peroxisome proliferator-activated receptor (PPAR?) to protect against cardiometabolic disorders. In addition, bilirubin can also inactivate glycogen synthase kinase-3? (GSK3?) to increase PPAR? target genes such as fibroblast growth factor 21 (FGF21); however, the specific roles of GSK3? inactivation/PPAR? activation to the anti-hypertensive, anti-steatotic and anti-diabetic actions of moderate hyperbilirubinemia are not known. Biliverdin reductase (BVR) is the enzyme responsible for reduction of biliverdin to bilirubin. It can generate bilirubin found in the plasma and generated inside the cell. The goal of this proposal is to test the central hypothesis that bilirubin and BVRA protect against obesity- induced hepatic steatosis, insulin resistance and hypertension via activation of the PPAR??signaling axis. Aim 1 will test the hypothesis that chronic moderate hyperbilirubinemia resulting from bilirubin treatment or antagonism of hepatic UGT1A1 lowers blood pressure and reverses dietary obesity-induced hepatic steatosis and hepatic insulin resistance. Aim 2 will test the hypothesis that moderate hyperbilirubinemia lowers blood pressure and reverses hepatic steatosis and insulin resistance via activation of PPAR?. Aim 3 will test the hypothesis that that specific loss of hepatic bilirubin generation enhances hepatic steatosis and insulin resistance through a GSK3??mediated pathway that decreases PPAR? activity. Findings of these studies will have profound implications on development of moderate hyperbilirubinemia as a novel therapy for treatment of obesity-induced cardiometabolic disease. These studies will also determine the novel role of bilirubin as a nuclear hormone receptor signaling molecule and the role of this mechanism in protection against obesity- induced cardiometabolic diseases such as hypertension, NAFLD and type II diabetes.